Diabetes is a rapidly growing global health problem. Patients with diabetes are frequently affected by neuro-vascular complications such as peripheral arterial disease (PAD) and diabetic neuropathy (DN). PAD is usually characterized by occlusive arterial disease of the lower extremities, and when advanced into the critical limb ischemia stage, can often lead to leg amputation. As advanced PAD in diabetes frequently affects small vessels, conventional percutaneous intervention and surgical treatment are ineffective in many cases. Diabetic neuropathy (DN) is the most common complication of diabetes, affecting 60% of diabetic patients. DN is characterized by damage to the neural vasculature as well as to neuronal cells. Despite the continuous increase in the incidence of these debilitating diseases, no current treatments effectively treat these conditions. Growing evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) are effective in treating various cardiovascular diseases and DN by inducing neovascularization. However, studies have reported that EPCs derived from diabetic subjects are dysfunctional, and therefore autologous cell therapy may have limited therapeutic effects. Recent evidence has suggested that even after achieving glucose control, diabetes can lead to long-term complications, and epigenetic chromatin alterations may underlie this metabolic memory of target cells. Other advances have been made that show the ability of small molecules to induce chromatin remodeling of affected genes and alter gene expression and cell phenotype. In addition, a bioengineering approach has been used to overcome the shortcomings of cell transplantation. Accordingly, we aim to investigate epigenetic chromatin changes in diabetic EPCs, and to reprogram and/or engineer diabetic EPCs with small molecular epigenetic regulators and biomaterial to enhance or restore their function. We will finally determine their therapeutic effects on well-established animal models of diabetic PAD and DN. We anticipate that this study will yield novel insight into the chromatin alterations of the EPCs in diabetes and suggest the potential therapeutic utility of modified EPCs for treating various diabetes-related neurovascular complications in an autologous manner. Given the safety of EPCs, this approach can be easily translated into a pilot clinical trial once the efficacy is established by this study. PUBLIC HEALTH RELEVANCE: Despite the ever-growing incidence of diabetic neuro-vascular complications such as advanced peripheral arterial disease (PAD) or critical limb ischemia, and diabetic neuropathy (DN), no treatments have yet to effectively treat these diseases. Growing evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) are effective in treating various cardiovascular diseases and DN by inducing vessel formation and protection from further neural damage;however, studies have reported that EPCs derived from diabetic subjects are dysfunctional, and therefore autologous cell therapy may have limited therapeutic effects. Accordingly we aim to identify the epigenetic changes of diabetic EPCs, and reprogram and/or engineer these diabetic EPCs with small molecular chemicals and biomaterials to enhance or restore their function for treating diabetic neurovascular complications.